This invention relates to a new, simplified method of preparing a known ketimine compound. Specifically, it is concerned with the synthesis of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene-]methanamine , a critical intermediate in the production of cis-(1S)(4S)-N-methyl-4(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthale neamine (sertraline). Sertraline hydrochloride is the active ingredient in the antidepressant Zoloft.
The most widely used route to date for the commercial preparation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine, leading to cis-(1S)(4S)-N-methyl4(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalen eamine (sertraline), involves a condensation reaction of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone with monomethylamine, which is catalyzed by titanium tetrachloride, as described by W. R. Welch, Jr. et al. in U.S. Pat. No. 4,536,518 and in Journal of Medicinal Chemistry, Vol. 27, No. 11, p 1508, 1984. However, the safety concerns (due to extreme reactivity with water) and hazardous by-products (namely, titanium dioxide monomethylamine hydrochloride) associated with use of titanium tetrachloride, have prompted evaluation of alternative dehydrating agents that would eliminate the formation of hazardous by-products. The advantages associated with elimination of solid by-product formation include not only improved safety, but also improved productivity associated with elimination of the need for filtration of the by-product from the reaction medium. The process of filtering titanium dioxide monomethylamine hydrochloride on common commercially available isolation devices is very time consuming.
An alternative route to N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenyl-idene-]methanamin e is described in U.S. Pat. No. 4,855,500 to J. C. Spavins, wherein the dehydration characteristics of appropriate mesh molecular sieves are employed to promote the condensation reaction between 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone and monomethylamine. The appropriate type molecular sieves (specifically, those having a pore size of about 3 Angstroms) are contacted in-situ with the mixture of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone and monomethylamine, and adsorb the water formed from the condensation reaction. Once the desired condensation reaction is essentially complete, forming N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene-]methanamine , the water saturated molecular sieves must be removed from the product containing solution by filtration prior to isolation of the ketimine product. Furthermore, used sieves must typically be regenerated if they are to be reused.
The process of this invention provides a novel and useful synthetic route to N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene-]methanamine , known to be a useful intermediate in the synthesis of sertraline. This novel route involves a condensation reaction between 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone and monomethylamine in a solvent such as an alkanol or a mixture of two or more alkanols. The nature of the solvent and the solubility of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalenylidene-]methanamine in the solvent are such that reaction equilibrium is favorably enhanced towards the ketimine product, namely N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene-]methanamine . The desired ketimine is thus produced in acceptable purity and high yield without requiring the addition of a heterogeneous catalyst, such as, for example, molecular sieves. This novel, one step approach to the synthesis of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene-]methanamine from 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone therefore avoids the above described disadvantages associated with the titanium tetrachloride route. Moreover, the need for addition of a dehydration agent (es, titanium tetrachloride or molecular sieves or another such dehydration promoting additive) is eliminated, as is the associated need for removal of by-products or spent sieves from the completed reaction mixture.